Background and Objectives: These studies explore the role of fludarabine as a therapeutic alternative for treatment-resistant autoimmune rheumatic diseases such as rheumatoid and soriatic arthritis, and systemic lupus erythematosus. The clinical efficacy, toxicity, and immunological effects of fludarabine are studied in patients with autoimmune rheumatic disorders in phase I/II clinical studies. Fludarabine primarily affects lymphoid cells because these cells have small amounts of the enzyme necessary to metabolize fludarabine. Previous investigations employing this drug in patients with low-grade lymphoid malignancies have shown that it selectively targets immune cells by inducing a physiologic form of cell death called apoptosis. However, it's effects on the clinical course of immunologic diseases, as well as on the function and regeneration of immune cells have not been characterized. Results 1) Rheumatoid Arthritis (RA) In a two dose (20 and 30 mg/m2) open label clinical trial 26 patients with severe RA refractory to treatment were treated with fludarabine for 6 months. Using intention to treat analysis, 17% of patients in the low dose group and 36 % in the high dose group met ACR criteria for 20% improvement. Significant lymphopenia involving both naive and memory T cells (naive<memory) and B cells were observed in all patients. No significant regeneration of naive T cells was observed after treatment suggesting limited thymic regenerative capacity. Despite the significant peripheral lymphopenia the number of lymphocytes infiltrating the synovium did not decrease. Fludarabine decreased the proliferative response of lymphocytes to mitogens as well as the production of the T cell derived cytokines IL-2 and IFN-gamma. In contrast to T cells, B cells maintained their ability to regenerate adequate numbers after therapy. During the study there were 4 episodes of localized H. Zoster infection, but no other significant complications. Based on this preliminary study, a phase II study (placebo controlled, masked, randomized) has been initiated in patients with severe RA with inadequate response to methotrexate alone. Patients are randomized to receive either fludarabine or placebo in addition to their methotrexate. To date, we have enrolled 4 patients in this study (out of 40 total). 2) Psoriatic Arthritis Patients failing at least one disease modifying agent have been randomized to receive either fludarabine or placebo for 4 months. So far we have enrolled 12 patients out of the 20 required for this study. In addition to toxicity and efficacy, synovial and skin biopsies are performed before and after treatment to monitor the effects of treatment on the biology of the disease. 3) Systemic lupus erythematosus Pulse cyclophosphamide therapy is the treatment of choice for severe lupus nephritis. Longer courses of cyclophosphamide (<15 pulses) significantly decrease the risk for subsequent relapses as compared to a shorter course (7 pulses) but are associated with higher rates of sustained amenorrhea (as high as 40% )for women 26-30 years of age. Time to complete remission in some patients may be as long as 3 years while some patients (up to 30%) may not achieve complete remission. In vitro data suggest that cyclophosphamide alkylates DNA while fludarabine interferes with its repair thus maximizing its efficacy. In contrast to cyclophosphamide fludarabine induces apoptotic death even in resting, non-proliferative lymphocytes. Patients with chronic lymphocytic leukemia refractory to fludarabine alone respond to combinations of this drug with fludarabine. More recently, fludarabine has emerged as an alternative option for patients undergoing bone marrow transplantation who are at high risk of complications from the routine myeloablative regimens. In this phase Ia/Ib study 15 patients with roliferative lupus nephritis will receive oral pulse cyclophosphamide in combination with subcutaneous fludarabine for 6 months. The cumulative dose of cyclophosphamide in this regimen is 5 gm compared to 30 gm used in the conventional treatment protocol. The primary objective of this study is to determine the tolerability of this regimen and to obtain preliminary information on its efficacy. To date, we have enrolled 2 patients in this study. Lay Summary Fludarabine is an adenosine analog which selectively targets lymphocytes, the cells which are thought to be responsble to cause tissue injury for a variety of autoimmune rheumatic diseases such as rheumatoid and psoriatic arthritis, and systemic lupus erythematosus. We have initiated a series of studies in patients with these diseases to explore their role as alternatives to treatment resistant diseases. In these studies fludarabine is used alone or in combination with other drugs such as methotrexate and cyclophosphamide. Initial studies in patients with rheumatoid arthritis have demonstrated an acceptable toxicity profile and have suggested a clinically significant therapeutic effect.